Metastatic prostate cancer (PCa) remains to be one of the leading causes of cancer-related death in U.S. men. Most tumors that advance to so-called metastatic castration-resistant PCa or mCRPC develop resistance to the 2nd generation therapeutics including enzalutamide, which is generally incurable. Numerous studies clearly indicate that androgen receptor (AR) plays a pivotal role in the disease progression. Importantly, AR mRNA and protein, including its alternatively spliced variants, are highly overexpressed in most CRPC tumors, which contribute majorly to resistance. Therefore, there is an urgent need of more effective therapeutics that can suppress the aberrant AR gene expression and provide sustained benefits to PCa patients. We recently discovered that RORg, a nuclear receptor family member and a drug target for human autoimmune diseases, is overexpressed and amplified in metastatic PCa. We further discovered that RORg-selective, small molecule inhibitors identified by us and others can potently inhibit tumor growth of CRPC xenograft models, without discernable adverse effects on host animals. Further studies revealed that RORg directly activates AR gene expression. In this application, we propose experiments to rigorously test the hypotheses that (1) RORg drives CRPC resistance through directly up-regulating AR and the tumor androgen synthesis program and that (2) targeting RORg by the RORg-selective inhibitors is efficacious for treatment of the therapy-resistant CRPC. We will first determine the functional mechanism of RORg in promoting AR gene expression. Using different models including PDXs, we will then examine the efficacy of the RORg inhibitors in blocking CRPC tumor growth and metastasis, and in sensitizing the tumors to the current therapeutics such as abiraterone and enzalutamide. We will also take genomics approach to unearth and define the role of RORg in control of tumor androgen synthesis and EMT programs. RORg has not been explicitly implicated in any type of cancers. Thus, this study will be ground- breaking in several ways. It will, for the first time, establish RORg as a major driver of lethal CRPC, its specific inhibitors as effective AR gene and tumor blockers, and thus establish RORg as a new cancer therapeutic target. It will also stir the interests of pharmaceuticals to re-purpose their anti- autoimmune RORg inhibitors as a new generation of PCa drugs.